Changing the Genetics of Immune Cells to Combat Autoimmune Diseases

“We’re right at the intersection of two fields that are exploding: T cell-based immunotherapy … and genome modification. Putting them together has been really exciting.” 

– Alex Marson, MD, PhD 

Scientists have long known that genes control the immune system, but exactly how remains a mystery. Alex Marson, MD, PhD, has spent more than a decade trying to solve that puzzle by exploring genetic circuits that regulate immune-cell function. Marson arrived at UCSF in 2013 as the beneficiary of a donor-funded initiative – the Sandler Fellows Program – that enables exceptionally promising young investigators to pursue research projects considered too high-risk for more traditional funding sources. 

Marson, an associate professor in the Department of Microbiology and Immunology and a researcher in the Diabetes Center at UCSF, believes that once scientists identify genetic causes of autoimmune diseases, they will be better positioned to develop cell-based therapies to treat them. He envisions that one day, clinician-scientists will gather T cells, for example, from a patient with type 1 diabetes, edit the cells’ genomes to make them prevent attacks on beta cells  – the insulin-producing cells in the pancreas that are compromised in diabetes – then return the cells to the body to prevent or arrest the disease. 

Working in collaboration with the Chan Zuckerberg Biohub and members of the Innovative Genomics Institute – a joint UCSF-UC Berkeley program co-directed by UC Berkeley Nobel laureate Jennifer Doudna, PhD – Marson has accelerated his research rapidly using new CRISPR technology. CRISPR-Cas9 is a game-changing genome-editing tool that allows genetic modification of almost any organism. Marson and his team devised a new strategy to precisely modify patients’ T cells using the tool, while others in the Diabetes Center – including Jeff Bluestone, PhD; Qizhi Tang, PhD; and Stephen Gitelman, MD – learn how to reinfuse cells back into affected individuals. 

Using approaches they’ve developed, scientists in Marson’s lab rewrite specific sequences in human T cells and investigate the biological effects. In 2017, they reported their findings about a genetic variant that has been shown to protect against type 1 diabetes. The group discovered that rather than occurring in a traditional gene, the variant shows up in a “switch” that controls when and how a key gene is turned on in immune cells. 

Moreover, CRISPR technology has the potential to solve some unanswered questions about HIV; for example, how the virus hijacks genes to infect T cells, its primary target. Working with Nevan Krogan, PhD, and others in the UCSF HIV research community, Marson’s team has been deleting human genes in T cells and discovering which genetic alterations render T cells resistant to HIV infection. Next, they will investigate the genetic programs that allow HIV to remain dormant in T cells, thereby eluding current antiretroviral treatments. Marson’s lab received a $1.6 million grant from biopharmaceutical giant Gilead Sciences, a global leader in sales of HIV treatments, to advance this cure-related research. 

Marson and his collaborators believe their research has far-reaching potential and ultimately will improve the lives of millions of children and adults affected by autoimmune diseases, cancer, and infections as new treatments are developed.

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